Triclosan and Antibiotics resistance

1. What is the biocide triclosan?

1.1 What are biocides?

The SCCS opinion states:

4. DEFINITIONS

According to the Directive 98/8/EC of the European Parliament
and Council of the 16 February 1998,
biocidal products are
defined as active substances and preparations containing one or
more active substances, put up in the form in which they are
supplied to the user, intended to destroy, render harmless,
prevent the action of, or otherwise exert a controlling effect
on any harmful organism by chemical or biological means.

Within the scope of this mandate, the proposition is to apply
the following definitions:

1.2 What is triclosan?

The SCCS opinion states:

3. INTRODUCTION

Triclosan is an
antimicrobial
agent that has been used for more than 40 years as an
antiseptic,
disinfectant or
preservative in
clinical settings, in various consumer products including
cosmetics, plastic materials, toys, etc. It has a broad range of
activity that encompasses many, but not all, types of
Gram-positive and Gram-negative non-sporulating,
bacteria, some
fungi (Jones et
al. 2000, Schweizer 2001), Plasmodium falciparum and Toxoplasma
gondii (McLeod et al. 2001). It has also been shown to be
ecotoxic, particularly to algae in aquatic environments
(Tatarazako et al. 2004). Additionally, it has been shown to
interfere with the cycling of nitrogen in natural systems
(Fernandes et al. 2008, Waller and Kookana 2009).

There are concerns that the widespread use of a low
concentration of triclosan
in various applications might lead to or select for
bacterial
resistance to
antibiotics.
Antibioticresistance has become an
increasingly serious problem worldwide, and the continued use of
biocides including
triclosan may exacerbate this problem. The main cause of
antibiotic resistance remains the use and misuse of antibiotics.
During the last decade, antibiotic resistance has increased in
bacterialpathogens leading to
treatment failures in both human and animal
infectious diseases
(Harbarth and Samore 2005; for reports see: EARSS Annual Report
2005, WHO 2007).

The safety of continued use of
triclosan in cosmetic
products has recently been assessed by the EU Scientific
Committee on Consumer Products (SCCP 2009). The SCCP emphasised
that this risk assessment
concerns only the toxicological profile of triclosan and that
before a final conclusion on the safety of triclosan in cosmetic
products can be reached, the potential development of
resistance to
triclosan and cross-resistance by certain micro- organisms must
be assessed. Earlier evaluations of triclosan, on the basis of
available data, EU Scientific Committees concluded that there
was no convincing evidence that triclosan poses a risk to humans
and environment by inducing or transmitting antibacterial
resistance (SSC 2002) as well as there was no evidence of
clinical resistance and cross-resistance occurring from the use
of triclosan in cosmetic products (SCCP 2006). Further
information was sought for an update of these
evaluations.

The present evaluation of
triclosan is based
both on the information submitted by COLIPA1 to SCCS and on
research published in peer-reviewed scientific journals. It aims
at determining whether the continued use of triclosan may be
associated to the development of
resistance in certain
micro-organisms. It also aims at identifying additional research
needs.

3.1. Scope

Triclosan is used as a
preservative in
consumer products including cosmetics, where the maximum allowed
concentration according to the EU Cosmetics Directive 76/768/EEC
is 0.3%. The SCCP has recently performed a
risk assessment of the
use of triclosan in cosmetic products. Although the present
mandate concerns the evaluation of a possible association
between the use of triclosan in cosmetic products and the
development of resistance
by certain micro-organisms, the SCCS has taken into account all
evidence available from all uses of triclosan to perform its
assessment. This is in line with the SCCP conclusions of 2006
(SCCP/1040/06) and it is scientifically sound as 1) cosmetic
uses of triclosan account for most of the total use of this
biocide in the EU
and 2) it is scientifically impossible at present to assess the
use of triclosan in
cosmetics only, without taking into account its uses in
otherAnu applications. In the absence of a clear answer,
research needs will be identified. The effect of triclosan on
microflora in the environment on the basis of published
literature will also be covered, since environmental
bacteria represent
a pool of antimicrobialresistance genes.

Most of the information provided here relates to
bacteria, since
studies of the effects of
triclosan on other
micro-organisms are scarce.

The purity of batches of
triclosan used in
personal care products since the 1970s is described in the Table
1 (SCCP 2009). These data were provided by COLIPA. The purity
and contaminants might be different in triclosan from other
sources.

Biocidal products that
contain triclosan as the
main antimicrobial are
usually complex formulations due to the lack of solubility of
this bisphenol. Components of the formulation might affect the
activity of triclosan positively (e.g. through synergism) or
negatively (e.g. antagonism). There is some information on the
effect of formulation components on
biocide activity
(Alakomi et al. 2006, Ayres et al. 1999, Denyer and Maillard
2002, Maillard 2005b), but by large this information is
restricted due to proprietory restrictions, or the lack of
understanding on how formulation components work in term of
antimicrobial potentiation.

In the scientific literature, where
triclosan activity has
been reported, there is little reference to the use of
formulation. Instead triclosan is often dissolved in a solvent
such as DMSO.

3.4. Mode of action

Chemical biocides are
generally considered to have multiple target sites against
microbial cells, although such interactions are concentration
dependent (Russell et al. 1997; Maillard 2005a). The bisphenol
triclosan is no
exception. At a sub-inhibitory concentration, triclosan was
found to profoundly affect
bacterial growth,
indicating a strong interaction with the bacterial targets,
despite the high concentration exponent of triclosan (McDonnell
and Russell 1999). At higher
concentrations, Gomez
Escalada et al. (2005a) observed that triclosan was both
rapid-acting and active at all phases of population growth,
although some marked differences in its lethality were
observed.

These observations substantiated earlier findings with
Staphylococcus aureus (Regos and Hitz 1974; Suller and Russell
2000). Inhibition of key metabolic pathway and synthesis (Regos
and Hitz 1974; McMurry et al. 1998b) might be part of the lethal
action mechanisms of
triclosan. Indeed,
triclosan was found to target specifically fatty acid synthesis
with the inhibition of the
enzyme enoyl reductase
(enoyl-acyl carrier protein reductase, FabI) (McMurry et al.
1998a). It acts as a potent irreversible inhibitor of FabI by
mimicking its natural substrate (Heath et al. 1998; Levy et al.
1999) and this inhibition has been described as being slow and
competitive (Heath et al. 1999). The propensity of triclosan to
inhibit fatty acid synthesis in Plasmodium falciparum and
Toxoplasma gondii (McLeod et al. 2001) has led to the
development of a number of antimalarial and antibacterial
pro-drugs based on triclosan (Mishra et al. 2008; Freundlich et
al. 2009).

The rapid action of
triclosan at a high
concentration might be indicative of membrane damage (Villalain
et al. 2001) and it is clear that fatty acid synthesis targeting
cannot solely explain the lethal effect of triclosan (Gomez
Escalada et al. 2005b). Triclosan membranotropic effects result
in destabilised structures compromising the functional integrity
of cell membranes without
inducing cell lysis (Villalain et al. 2001). Intercalation of
triclosan into bacterial
cell membranes is likely to compromise the functional integrity
of those membranes, thereby accounting for some of triclosan
antibacterial effects (Guillén et al. 2004).

Recently, the first genome-wide transcriptional analysis of
Staphylococcus aureus exposed to
triclosan (0.05 μM),
reported that triclosan down regulated primary
metabolism-related and carbohydrate transport, the cap operon
which is essential for virulence, the clpB chaperone-related
genes which might
trigger the expression of
resistant
determinants, genes involved in fatty acid production and
utilisation (Jang et al. 2008).

A number of factors affect the
antimicrobial activity
of triclosan. These can be
divided into intrinsic factors derived from the
biocide and its
application (e.g. concentration, contact time, pH) and extrinsic
factors which derive from the environment during application
(e.g. temperature, soiling). Understanding the complex
relationship between concentration and contact time (sometimes
referred to as CT concept) is crucial to ensure efficacy
(Maillard 2005a). The stability of triclosan in particular
environments will also influence efficacy.